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- Volume 2, Issue 6, 2005
Medicinal Chemistry Reviews - Online (Discontinued) - Volume 2, Issue 6, 2005
Volume 2, Issue 6, 2005
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Development of Cancer Vaccine Targeting WT1 Product which is Expressed in Various Kinds of Malignant Neoplasms
Authors: Y. Oka, A. Tsuboi, O. A. Elisseeva, H. Nakajima, Y. Oji and H. SugiyamaThe Wilms' tumor gene WT1 is highly expressed not only in hematopoietic malignancies, including leukemia and myelodysplastic syndromes (MDS), but also in various kinds of solid tumors, including lung, breast, and colorectal cancer. Human cytotoxic T lymphocytes (CTLs) which could specifically lyse WT1-expressing tumor cells with HLAA* 0201 or HLA-A*2402 restriction were generated in vitro. We have also demonstrated that mice immunized with the WT1 peptide rejected challenges by WT1-expressing tumor cells and survived with no signs of auto-aggression to normal organs which physiologically expressed WT1 both in prophylactic and therapeutic models. Furthermore, we and others recently detected IgM and IgG WT1 antibodies in the patients with hematopoietic malignancies, indicating that WT1 protein was highly immunogenic, and that WT1-specific cellular immune responses that induce immunoglobulin classswitch of WT1 antibodies were elicited in the patients. These results provided us with the rationale for elicitation of CTL responses targeting the WT1 product for cancer immunotherapy. On the basis of the findings mentioned above, we performed a phase I clinical trial of WT1 peptide cancer vaccine for the patients with malignant neoplasms. It was demonstrated that WT1 peptide cancer vaccine had efficacy in the clinical setting, because reduction of leukemic blast cells, decrease of tumor markers, or regression of tumor masses was observed after the WT1 vaccination in patients with hematopoietic malignancies or solid cancers.
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Neuronal Nicotinic Receptors and Neuroprotection: Newer Ligands May Help us Understand their Role in Neurodegeneration
Authors: M. J. O'Neill, P. Astles, C. P. Dell, M. Keenan, T. K. Murray, V. Lakics, N. P. Visanji and S. DutyIn the last five-six years there has been a rapid increase in publications reporting that neuronal nicotinic acetylcholine receptors (nAChR) play a role in neurodegenerative disorders. Furthermore, there is a well-established loss in nAChR in post-mortem brains from patients with Alzheimer's disease, Parkinson's disease and a range of other disorders. In the present review we discuss (1) the new pharmacological ligands for studying neuronal nicotinic receptors and (2) evidence that nicotine and subtype selective nAChR ligands can provide neuroprotection in vitro in cell culture systems and in vivo using animal models of such disorders. This review is an up-dated and revised version of an earlier review published in Current Drug Targets - CNS and Neurological Disorders 4, 399-411, 2002. In terms of developing new drugs for nicotinic receptors, researchers at Abbott Laboratories have discovered a series of pyridyl ether analogues that are potent, full agonists of the α4β2 receptor. Sanofi-Synthelabo reported that SSR 591813 is a novel and selective partial α4β2 agonist, while Targacept have extensively evaluated the SAR of nicotine and metanicotine in their laboratories and developed a novel ligand, TC-2559. The α4β2 partial agonist profile of cytisine has led researchers at Pfizer to explore the potential of cytisine analogues in the treatment of addiction, in particular smoking cessation. These efforts have led to the discovery of CP-526555 (7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino[2,3-h] [3]benzazepine (2R,3R)-2,3-dihydroxybutanedioate, varenicline). There has also been a huge increase in the patent literature on α7 selective ligands. In the present review we summarise work from Astra, Pharmacia, Sanofi-Synthelabo and Bayer. Whilst in vitro data pertaining to a protective effect of nicotine against nigral neurotoxins like MPTP is less robust, most studies agree that nicotine is protective against glutamate and β-amyloid toxicity in various culture systems. This effect appears to be mediated by α7 subtype nAChR since the protection is blocked by α-bungarotoxin and is mimicked by α7 selective agonists. In vivo studies indicate that α7 receptors play a critical role in protection from cholinergic lesions and enhancing cognitive function. The exact subtype involved in the neuroprotectant effects seen in animal models of Parkinson's disease is not clear, but in general broad spectrum nAChR agonists appear to provide protection, while α4β2 receptor agonists appear to provide symptomatic improvements. Evidence favouring a protectant effect of nicotine against acute degenerative conditions is less strong, though some protection has been observed with nicotine pre-treatment in global ischaemia models. A variety of cellular mechanisms ranging from the production of growth factors through to inactivation of toxins and antioxidant actions of nicotine have been proposed to underlie the nAChR-mediated neuroprotection in vitro and in vivo. In summary, although until recently the lack of subtype selective ligands has hampered progress, it is clear that in the future neuronal nAChR agonists could provide functional improvements and slow or halt the progress of several crippling degenerative diseases.
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Cognition-Enhancing Drugs in Mild Cognitive Impairment (MCI) and Alzheimer's Disease (AD): An Update [1]
Authors: Fulvio Gualtieri, Luca Guandalini, Dina Manetti, Elisabetta Martini and Maria N. RomanelliCognition enhancers are drugs able to facilitate attentional abilities and acquisition, storage and retrieval of information, and to attenuate the impairment of cognitive functions associated with head traumas, stroke, age and agerelated pathologies such as MCI and AD. Development of cognition enhancers is still a difficult task because of the complexity of the brain functions, poor predictivity of animal tests and lengthy and expensive clinical trials. Current research is based on several working hypotheses, derived from the progress of knowledge in the neuro-bio-pathology of cognitive processes. Approaches followed to develop cognition enhancing drugs, the results obtained in the past few years (since 2000) and the most promising molecules under study are reviewed.
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Novel Agents in Anticancer Drug Therapy I (Antiangiogenic Agents, Egfr Inhibitors)
More LessThis report is the first part of an updated review of a previous survey published in this journal (2002, 2, 419-439). Since the discovery of the Human Genome Project dramatically increased our knowledge in regard of the mutated cancer cell, it is worthy to follow up those findings, that have brought progress in the therapy of malignant diseases. The molecular targeted drug therapy with transtuzumab or imatinib produced great initial success and several other candidate agents are now available for cancer treatment. This review summarises the antitumour effect of compounds under clinical testing. In the extracellular space, antiangiogenic molecules inhibit the metastasis production. Anti-MMP-s currently investigated are listed, followed by drugs designed to block endothelial proliferation. Membrane receptor blockers, signal transduction inhibitors, DNA replication inactivators, revertants and apoptosis inducers act in the intracellular space. Amongst these, proteasome inhibitors are of particular interest. This part of the review deals only with antiangiogenic products and the membrane receptor inhibitors. All other agents will be reviewed in the next part of this publication.
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Proteinases of Trypanosoma cruzi: Potential Targets for the Chemotherapy of Chagas Disease
More LessTrypanosoma cruzi, the agent of the American Trypanosomiasis, Chagas Disease, contains cysteine, serine, threonine and metallo proteinases. Aspartic proteinases have not been found so far. The most abundant among these enzymes is cruzipain, a cysteine proteinase expressed as a complex mixture of isoforms by the major developmental stages of the parasite, including some membrane-bound isoforms. The enzyme is an immunodominant antigen in human chronic Chagas disease and seems to be important in the host/parasite relationship. Inhibitors of cruzipain kill the parasite and cure infected mice, thus making the enzyme a very promising target for the development of new drugs against Chagas disease. In addition, 30 kDa cathepsin B-like enzymes have been described. Serine peptidases described in the parasite include oligopeptidase B, a member of the prolyl oligopeptidase family involved in Ca2+-signaling during mammalian cell invasion; a prolyl endopeptidase (Tc80), against which inhibitors are being developed, and a serine carboxypeptidase, belonging to the S10 family. Metalloproteinases homologous to the gp63 of Leishmania spp. are also present. The proteasome has properties similar to those of other eukaryotes, and its inhibition by lactacystin, blocks some differentiation steps in the life cycle of the parasite.
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Biological Characteristics and Role of Histamine in Case of Allergic Rhinitis
Authors: Md. T. Raza and De-Yun WangHistamine exerts its biological effect an humans through interaction with four histamine receptors (H1R, H2R, H3R and H4R). Histamine is a major mediator of allergic rhinitis (AR) that produces classical symptoms (sneezing, itching, rhinorrhea and congestion) both in adults and children. Nasal itch, sneezes, and rhinorrhoea are predominantly neural, while congestion is predominantly vascular. Antagonism of H1 receptors reduces majority of AR symptoms, which act primarily by the reversible and competitive inhibition of histamine action at H1R. To date, antihistamines are among the most commonly used pharmacological treatments in AR. This paper reviews the characteristic of histamine and histamine receptors in humans and the implication of antihistamine on AR.
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Macrolide Resistance in Mycobacteria
Authors: F. Doucet-Populaire, K. Buriankova, J. Weiser and J.- L. PernodetThe genus Mycobacterium contains two of the most important human pathogens, Mycobacterium tuberculosis and Mycobacterium leprae, the etiological agents of tuberculosis and leprosy, respectively. Other mycobacteria are mostly saprophytic organisms, living in soil and water, but some of them can cause opportunistic infections. The increasing incidence of tuberculosis as well as infections with non-tuberculous mycobacteria (NTM) in immuno-compromised patients has renewed interest in molecular mechanisms of drug resistance in these pathogens. Mycobacteria show a high degree of intrinsic resistance to most common antibiotics. For instance, species from the M. tuberculosis complex (MTC) are intrinsically resistant to macrolides. Nevertheless, some semi-synthetic macrolides as clarithromycin, azithromycin and most recently the ketolides, are active against NTM and widely used for infection treatment. However, shortly after the introduction of these new drugs, resistant strains appeared due to mutations affecting the macrolide target, the ribosome. The mycobacterial cell wall is considered to be a major factor in promoting the natural resistance of mycobacteria to various antibiotics. However, recent data show that specific macrolide resistance determinants (erm genes) are present in some species. This mini-review summarizes the current knowledge on the natural and acquired macrolide resistance in mycobacteria, gives an overview of potential mechanisms implicated in the intrinsic resistance and of macrolide resistance determinants in mycobacteria.
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